NMDA Receptors and NMDA Receptor Subunits
Glutamate and aspartate play dual roles in the central nervous system as essential amino acids and as the principal excitatory neurotransmitters (hereinafter referred to as excitatory amino acids or EAAS). There are at least four classes of EAA receptors: NMDA, AMPA (2-amino-3-(methyl-3-hydroxyisoxazol-4-yl)propanoic acid), kainate and metabotropic receptors. These EAA receptors mediate a wide range of signaling events that impact all physiological brain functions. For example, it has been reported that NMDA receptor antagonists produce an analgesic effect under certain conditions (Wong, C. S., Cherng, C. H. and Ho, S. T., Clinical Applications of Excitatory Amino Acid Antagonists in Pain Management Acta Anaesthesiologica. Sinica; 33, 227-232 (1995)).
The NMDA receptor is an ion channel permeable to Na+ and Ca2+. The receptor is gated by synaptically released glutamate in the presence of co-agonist glycine and concomitant depolarization (Mayer, M. L. and Westbrook, G. L., The Physiology of Excitatory Amino Acids in the Vertebrate Nervous System, Progress in Neurobiology, 28, 197-276 (1987)). Thus, NMDA receptor activity may be attenuated by blockade, for example, of 1) the glutamate binding site, 2) the glycine co-agonist binding site, or 3) the site of the ion channel.
The NMDA receptor is composed of multiple protein subunits (Seeburg, P. H., The Molecular Biology of Mammalian Glutamate Receptor Channels, Trends in Neurosci., 16, 359-365 (1993)). The protein subunits fall into two categories: NR2 and NR1. The NR2 subunits contain glutamate binding sites, whereas the NR1 subunits contain the glycine binding sites. Five subunits have been cloned to date, namely NR1 and NR2A, NR2B, NR2C and NR2D. Expression studies indicate the functional receptor is composed of at least one NR1 site and one or more of the NR2 sites. Thus, different subtypes of NMDA receptors can be categorized based on their particular NR2 subunit composition. For example, in the adult mammalian brain, the NR1 and NR2A subunits are widely expressed, forming a subtype of NMDA receptor comprising an NR2A subunit. In contrast, NR2B subunit expression is mostly localized in forebrain regions including cortex, hippocampus and striatum; the NR2C subunit is expressed in the cerebellum; and the NR2D subunit is restricted to the midbrain region. NMDA receptor subtypes of corresponding composition can accordingly respectively be found in forebrain, cerebellum, and midbrain.
Compounds that inhibit NMDA receptor activity by interacting at the glutamate, glycine, or receptor-associated ion channel as described above have little (<10-fold) selectivity across the different NMDA receptor subtypes. That is, such compounds inhibit NMDA receptors with potencies within a 10-fold range regardless of the subunit combination. However, the subunit composition of the NMDA receptor can confer unique physiology with regard to conductance, kinetics, and affinity for certain agonists. For example, the subunit composition of an NMDA receptor has significant effects on its sensitivity to a group of allosteric modulators which include protons, polyamines, Zn2+, and oxidizing/reducing agents (Chenard, B. L. and Menniti, F. S., Antagonists Selective for NMDA Receptors Containing the NR2B Subunit, Current Pharmaceutical Design, 1999, 5:381-404)). Receptors comprising the NR2B subunit possess a unique site to which compounds may bind, resulting in specific inhibition this subtype of NMDA receptor as compared to NMDA receptors that do not comprise an NR2B subunit (Ibid). This unique site is distinct from the glutamate binding site on the NR2B subunit.
Antagonizing NMDA receptors at the NR2B subunit specific binding site can be used to substantially avoid side effects that have been noted at therapeutic drug levels with other non-specific NMDA receptor antagonists. Both glutamate competitive antagonists and channel blocking agents cause cardiovascular effects and psychotic symptoms in man (Chenard and Menniti, supra). In rodents, these types of compounds also cause locomotor hyperactivity and a paradoxical neuronal hyperexcitability manifest as neuronal vacuolization in cingulate and retrosplenial cortices (Id.). Antagonists at the glycine co-agonist site cause less locomoter activation and do not cause neuronal vacuolization at neuroprotective doses in rodents, however physicochemical problems (for example, problems relating to solubility, brain penetration and protein binding) associated with the quinoxalinedione nucleus typical of such compounds have hindered efforts to bring this class of molecules forward in the clinic (Id). NMDA receptor antagonists selective for the NR2B subunit offer a means of inhibition without the side effects and psychochemical difficulties described above.
NR2B Subunit Selective NMDA Receptor Antagonists
Compounds that inhibit NMDA receptors comprising an NR2B subunit by specific binding to the NR2B subunit have been demonstrated by measurement of inhibition of NMDA-induced current in Xenopus Oocytes cotransfected with the genes expressing the NR1 and NR2B subunits (Chenard and Menniti, supra). Specificity for NR2B can be confirmed by observing reduced inhibition of the NMDA-induced current in Xenopus Oocytes cotransfected with an NR1 subunit and an NR2 subunit other than NR2B.
A number of compounds have been found to act as antagonists that target the NR2B subunits of NMDA receptors that contain them. The first compound identified to display significant affinity for the NR2B subunit was ifenprodil. Ifenprodil is both more potent and efficacious for blockade of ion current through NMDA receptors comprised of NR1/NR2B subunits compared to NR1/NR2A, NR2C, or NR2D subunits.
For example, ifenprodil and related compounds have been demonstrated in animal models of pain perception to produce significant analgesic activity (Bernardi, M., Bertolini, A., Szczawinska, K. And Genedani, S., Blockade of the Polyamine Site of NMDA Receptors Produces Antinociception and Enhances the Effect of Morphine, in Mice, European Journal of Pharmacology, 298, 51-55, (1996); Taniguchi, K., Shinjo, K., Mizutani, M., Shimada, K., Ishikawa, T., Menniti, F. S. and Nagahisa, A, Antinociceptive Activity of CP-101,606, an NMDA Receptor NR2B Subunit Antagonist, British Journal of Pharmacology, 122, 809-812 (1997)).
U.S. Pat. No. 5,710,168 (issued Jan. 20, 1998) claims the use of certain compounds of formula I, infra, having NR2B subunit selectivity for treating a disease or condition which is susceptible to treatment by blocking of NMDA receptor sites, including traumatic brain injury, spinal cord trauma, pain, psychotic conditions, drug addiction, migraine, hypoglycemia, anxiolytic conditions, urinary incontinence, and ischemic events arising from CNS surgery, open heart surgery or any procedure during which the function of the cardiovascular system is compromised.
U.S. Ser. No. 09/397,891, filed Sep. 17, 1999, pertains to a method of treating acute, chronic and/or neuropathic pain comprising administering an NR2B selective NMDA receptor antagonist, for example a compound of formula I, infra.
U.S. Pat. No. 5,710,168 and U.S. Ser. No. 09/397,891 are both incorporated by reference herein in their entireties.